Phosphatidylinositol-3 kinase and extracellular signal-regulated kinase mediate the chemotactic and mitogenic effects of insulin-lice growth factor-I in human hepatic stellate cells

被引:69
作者
Gentilini, A [1 ]
Marra, F [1 ]
Gentilini, P [1 ]
Pinzani, M [1 ]
机构
[1] Univ Florence, Dipartimento Med Interna, I-50134 Florence, Italy
关键词
cell migration; cell proliferation; liver fibrosis; platelet-derived growth factor;
D O I
10.1016/S0168-8278(00)80067-7
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background/Aim: Several studies have shown that proliferation of hepatic stellate cells is stimulated by insulin-like growth factor-I. The aim of this study was to investigate the effect of insulin-like growth factor-I on human hepatic stellate cells chemotaxis and the intracellular pathways involved in both mitogenic and chemotactic effects. Methods/Results: Insulin-like growth factor-I, at the concentration of 100 ng/ml, was able to induce a 2- to 3-fold increase in human hepatic stellate cells migration in a modified Boyden chamber system. This effect was associated with a marked activation of phosphatidylinositol 3-kinase by insulin-like growth factor-I, as evaluated by measurement of phosphatidylinositol 3-kinase activity in phosphotyrosine immunoprecipitates. In order to establish a functional link between these observations,,ve then performed experiments employing two selective phosphatidylinositol 3-kinase inhibitors, namely wortmannin and LY294002. These compounds blocked activation of phosphatidylinositol 3-kinase and inhibited insulin like growth factor-I-induced hepatic stellate cells migration. Since phosphatidylinositol 3-kinase activation has been shown to be necessary for platelet-derived growth factor-induced mitogenesis in hepatic stellate cells, we verified the effects of phosphatidylinositol 3-kinase inhibition on insulin-like growth factor-I-induced DNA synthesis. Incubation with either wortmannin or LY294002, dose-dependently reduced the mitogenic potential of insulin-like growth factor-I. Since phosphatidylinositol 3-kinase is involved, at least in part, in the activation of the Ras/extracellular signal-regulated kinase pathway in hepatic stellate cells, the role of extracellular signal-regulated kinase activation in mediating the biological effects of insulin-like growth factor-I was explored. Insulin-like growth factor-I induced mitogenesis and chemotaxis were markedly reduced by pre-incubation of hepatic stellate cells with PD-98059, a selective inhibitor of MEK. Conclusions: Activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase is required for both insulin-like growth factor-I-dependent hepatic stellate cells proliferation and chemotaxis. Insulin-like growth factor-I, together with other soluble mediators, may contribute to the hepatic mound-healing response by modulating hepatic stellate cells migration and proliferation.
引用
收藏
页码:227 / 234
页数:8
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